Although African Americans are at elevated risk for age-related cognitive decline and memory loss? with double the prevalence of Alzheimer's disease (AD) compared to white Americans?we do not sufficiently understand the causes of this health disparity, nor how to best focus future interventional efforts to remediate this health crisis among older African Americans. Stress, sleep deprivation, sedentary lifestyles, poor cardiovascular fitness, depressive symptoms, high body mass, and low education are all known risk factors for cognitive decline and AD; their widespread presence among African Americans, particularly in low socioeconomic communities, suggests that some or all of these may be key to the high rates of dementia and Alzheimer's among African Americans. However, little is known about the relative importance (and interactions) among these different risk factors for AD in African Americans. Additionally, there is a dearth of data on the neural changes that occur across the lifespan in older African Americans-- especially those at highest risk for AD-- and how these relate to behavioral and lifestyle risk factors for AD. This revised R01 resubmission?including four months of pilot data from our R56 bridge award and retitled ?Risk Factors for Future Cognitive Decline and Alzheimer's Disease in Older African Americans??will address the aforementioned gaps in understanding minority health disparities in Alzheimer's disease. We will test 360 African Americans, ages 65-85, on a battery of neuropsychological, cognitive, health, fitness, genetic, and lifestyle assessments. Our sample includes 240 newly recruited participants as well as 120 legacy participants recruited during the current R56 grant. Half (180) will receive brain imaging using MRI, addressing the paucity of available neuroimaging data on older African Americans. Two aspects of our plans are especially innovative and significant to project success. First, we address barriers to African-American research participation and retention through our ten-year history of partnership, cooperation, and trust with the African-American communities of Greater Newark through Rutgers University-Newark's African American Brain Health Initiative: A University-Community Partnership (www.brainhealth.rutgers.edu). Our long-term relationships with community-based organizations have been critical to our past successes and involve year-round programs for community outreach, education, and engagement that bolster our research recruitment and retention. Many of these efforts are funded through a five-year grant to the PI from the NJ Department of Health's Office of Minority and Multicultural Health. Second, we address the need for evaluating and validating novel cognitive assessments that are sensitive to the earliest stages of prodromal Alzheimer's disease by having all participants complete the Rutgers Generalization Tasks, innovative cognitive assessments developed by the Co-I (Myers) and PI (Gluck). These tasks are derived from prior neurocomputational models of the entorhinal cortex (EC) and hippocampus, brain regions disrupted in the earliest stages of prodromal AD. As these tasks are based on non-verbal animal conditioning paradigms, they may be especially valuable for tracking cognitive changes in our population, which is affected by low levels of education or verbal fluency. We hypothesize that deficits in generalization?the ability to apply previously learned rules to novel task demands and new stimuli?will correlate with, and longitudinally predict, cognitive decline and neural changes in prodromal AD. Aim #1. CROSS-SECTIONAL BEHAVIORAL ANALYSES: We will evaluate (1) how variations in health, physical fitness and activity are correlated with cognitive function, and (2) how the influence of these variables is mediated by education, social support, and genetics, in modulating the risk of cognitive decline and AD in elderly African Americans.!Predictions: Low levels of physical activity and cardiovascular fitness and high body mass, will be correlated with poorer performance on the Rutgers Generalization Tasks. Aim #2. NEURAL MECHANISM ANALYSES: Using multimodal MRI to capture brain structure, function, and white matter integrity, we evaluate how the relationships in Aim #1 are mediated by neural mechanisms. Predictions: Poorer generalization performance (and low levels of physical activity and fitness) will be associated with reduced hippocampal volume, entorhinal cortical thickness, intra-hippocampal and EC- hippocampal connectivity, and decreased FA and increased MD in the hippocampus and EC. Aim #3. LONGITUDINAL PREDICTIVE ANALYSES: To identify longitudinal aspects of the relationships described in Aim #1 and Aim #2, along with predictors of future cognitive decline and progression to aMCI and AD, we will test all participants at baseline and every two years thereafter (providing us data from three time-points for the legacy R56 cohort, and two time-points for the newly recruited participants). Predictions: Participants who progress to aMCI or AD will show early impairments on the generalization tasks (correlated with neurodegeneration) prior to deficits in standardized memory assessments, as well as being more likely to have a history of lower physical activity and poorer cardiovascular fitness. The proposed R01, building on our ongoing R56 data collection, will overcome current limitations to understanding the high rate of cognitive decline and AD in older African Americans, while providing further clinical and neuroimaging validation of innovative cognitive assessments, the Rutgers Generalization Tasks, which may prove useful for detecting and measuring cognitive changes in early prodromal AD.